The overarching goal of this competing renewal K24 Mid-Career Investigator Award in Patient-Oriented Research is to enhance training in clinical multidisciplinary research focused on environmental health at Yale, building upon the substantial progress made during the initial K24 award. The candidate, Carrie A. Redlich, MD, MPH, is a highly respected and productive clinical investigator with unique training and research experience in multidisciplinary environmental/occupational health research. This proposal will enable Dr. Redlich to expand her current research efforts focused on understanding the health effects of isocyanate exposures, enhance her own research skills, and greatly advance her mentorship program. The research plan includes currently supported multidisciplinary studies investigating the effects of exposure to hexamethylene diisocyanate (HDI) in auto body shop workers, risk factors, mechanistic pathways and preventive approaches. New research specifically supported by this K24 award will focus on diphenylmethane diisocyanate (MDI), the most commonly used isocyanate worldwide. It builds upon the substantial progress to date and a long-standing relationship with Uretek, a fabric coating company in New Haven that uses MDI in the production of polyurethane coating fabrics, and will address important questions concerning the biologically relevant antigenic form of MDI, the role of skin exposure, exposure-dose relationships, and host factors. The specific aims are: AIM 1) Identify and characterize biologically relevant antigenic forms of MDI. AIM 2) Evaluate the respiratory and health status of individual workers at Uretek. AIM 3) Characterize individual MDI skin and respiratory exposure patterns at Uretek. AIM 4) Characterize the effects of MDI exposure on gene and protein expression profiles using DNA microarray and proteomic analyses. AIM 5) Integrate exposure, clinical, immunologic, physiologic, and demographic data with genomic and proteomic data to explore exposure disease associations and host susceptibility factors which modify risks of exposure. Importantly, this new project will also serve to advance Dr. Redlich's research skills in new areas and provide a unique opportunity to mentor junior.